It is becoming clear that one of the very realistic and attainable goals of modern genetics is to identify in detail the genetic factors in people that correlate with human health. From inherited diseases to drug efficacy to the specific genetic changes occurring during tumor development, medical genetics promises a profound impact on the state of human health. Although the enormity of the task of sorting thorough millions of genetic differences (SNPs) to find the few or several that underlie a particular health factor at first draws inconceivable, the reality is that not only is such a feat conceivable, it has already started. Our focus has been on the genetics of the immune response as that is obviously a subset of human genetics most relevant to human health. To expand the potential for study, we have determined the genomic sequence of the Killer cell Ig-Iike receptor (KIR) locus. The cell surface expressed KIR gene products interact directly with HLA class I molecules to regulate the activity of natural killer cells and to a smaller degree, T cells. Analogous to HLA class I and II, the KIR genes have significant allelic polymorphism, although unlike HLA almost no functional examination of these polymorphisms has been carried out. We have been deciphering haplotypic variation at KIR in order to establish a primary level of variation. These data are being combined with second level allelic variation to establish detection methodologies amenable to the unique characteristics of this gene family. In order to study the involvement of KIR in the outcome of marrow transplant specifically and immune related genetic effects in general, we propose to accomplish the following specific aims: I) To identify and characterize new haplotypes and allelic polymorphisms in the killer cell Ig-Iike receptor genomic locus. This will be accomplished by utilizing existing high- throughput genomic analysis on family and existing cell line DNAs. 2) To develop and define a set of data and technologies useful as mapping tools for the study of potential KIR-Iinked diseases. To accomplish this we will define and relate KIR haplotype frequencies, allelic linkage disequilibria, recombination frequency, and location relative to existing and new genes from a spectrum of ethnic groups. 3) To carry out KIR-based analysis of marrow transplant populations and the relationship of KIR haplotypes to In HLA haplotypes. By utilizing this knowledge it should then be possible to carry out pilot studies on well-defined panels of patient-donor pairs in order to test the hypothesis that genetic factors outside of the MHC and associated with KIR can affect transplant outcome.